The invention relates to methods and means useful for the early detection of vascular disease, such as atherosclerosis, particularly, methods and means employing labelled synthetic peptides to detect arterial injury.
Atherosclerosis is a disease which causes the thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions or raised fibrous plaques which form within the arterial lumen. The plaques are most prevalent in the abdominal aorta, coronary arteries, or carotid arteries, and they increase progressively with age. They commonly present dome-shaped, opaque, glistening surfaces which distort the lumen. A lesion typically will consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits and exhibit various degrees of necrosis, thrombosis, and ulceration.
The injury at, or deformities of, the arterial lumen presented by the plaque and associated deposits result in occluded blood flow, and ultimately in angina, cerebral ischemia, renal hypertension, ischemic heart disease, stroke, and diseases of other organs, if untreated. At present, coronary atherosclerosis is still the leading cause of death in the United States, claiming the lives of over a half million Americans annually, roughly twice as many as are killed by cancer.
Unfortunately, there are no existing diagnostic methods which can detect the early stages of atherosclerosis and related vascular diseases which often are clinically silent. Since lifestyle changes, drug therapy, and other means exist for delaying or reducing vascular occlusion or the stresses on various body organs which result from atherosclerotic lesions, the early detection of atheromatous plaques in the vascular system would be of considerable value in permitting preventive intervention at a time when it can be most effective.
Arteriography, the conventional approach to diagnosing vascular disease, involves catheterization and the injection of radiopaque substances into the bloodstream in order to image obstructions in the arteries. This procedure involves significant morbidity, in that infection, perforation of the artery, arrhythmia, stroke, infarction, and even death can occur. Because of the risks involved, arteriograms typically are reserved for individuals with advanced or acute atherosclerotic disease.
A variety of less invasive techniques for the diagnosis of vascular injury and disease have been proposed. These techniques include plethysmography, thermography, and ultrasonic scanning (Lees and Myers, Adv. Int. Med. 27:475, 1982).
Other non-invasive approaches to the diagnosis of vascular injury which have been proposed by the present inventor involve the administration of labelled target-seeking biologically active molecules or antibodies which preferentially seek out arterial lesions (U.S. patent application Ser. No. 929, 012, entitled "Detection of Vascular Disease", filed Nov. 10, 1986) and the administration of labelled low density lipoproteins (LDLS) to the vascular system of a patient (U.S. Pat. Nos. 4,647,445 and 4,660,563). LDLs circulating in the blood are known to bind to atherosclerotic plaques (Lees et al., J. Nucl. Med. 24:154, 1983). This binding most likely occurs via apolipoprotein B-100 (apo B-100), the protein moiety of the LDL molecule, which is responsible for the removal of LDL from the circulation by receptor-mediated uptake in a variety of cell types. LDLs conjugated to a radioactive label can be used to provide information on the location and extent of plaque in the vascular system by imaging them with a radiation detector. Alternatively, LDLs can be labelled with a non-radioactive, paramagnetic contrast agent capable of detection in magnetic resonance imaging (MRI) systems.
One disadvantage to this method is that several days are typically required to isolate LDLs from the patient's blood and to label them. Often, such a delay in diagnosis and subsequent treatment is detrimental for critically ill patients. Further, an additional risk of viral infection is incurred if donor blood is employed as an LDL source.
Consequently, there exists a need for better noninvasive techniques and reagents capable of detecting and mapping early, non-stenosing, non-flow-disturbing atherosclerotic arterial lesions.
Accordingly, it is an object of the present invention to provide synthetic peptides which are useful for detecting and imaging vascular disease or injury.
It is another object of the invention to provide synthetic peptides useful for imaging which are inexpensive and easy to prepare.
It is yet another object of the invention to provide an improved method of detecting and mapping vascular injury, including vascular injury at its early stages.
Yet another object of the present invention is to provide a method, which is non-invasive, of detecting and mapping vascular injury.
Finally, it is an object of the present invention to provide synthetic peptides for the prevention or treatment of vascular damage.